tbuckley/cabot-search huggingface dataset:
INNV-40. DURABLE 10-YEAR RESPONSE TO VEMURAFENIB IN A PATIENT WITH CNS HAIRY CELL LEUKEMIA
Authors: Yi Li, Jan Drappatz, Megan Mantica
Journal: Neuro-Oncology (2023)

Abstract Hairy cell leukemia (HCL) is an uncommon form of chronic B-cell lymphoproliferative disease, accounting for approximately 2% of all cases of leukemias. Although there have been rare instances of HCL affecting the central nervous system (CNS), these cases usually involve highly fatal leptomeningeal disease or direct leukemic infiltration into the brain. The BRAF V600E mutation, leading to the constitutive activation of the MAPK/ERK signaling pathway, is recognized as a key activating mutation in HCL and is present in almost all HCL patients. First-line treatment for HCL remains purine analogs; however, up to 20% of patients only achieve a partial response. Vemurafenib, an oral inhibitor of BRAF V600E, has demonstrated strong anti-tumor activity in patients with systemic relapsed/refractory HCL and has good CNS penetration. In this case study, we present a 67-year-old patient with HCL who initially presented with multifocal cranial neuropathies In August of 2013. His brain MRIs demonstrated multiple enhancing leptomeningeal foci. While a combination of cytarabine, methotrexate, and rituximab initially prevented disease progression, he experienced multiple relapses over the course of 2 years and eventually became refractory to treatment. Subsequently, the patient was started on vemurafenib, which resulted in the complete resolution of all lesions observed on MRIs. This response has persisted for 10 years since starting the medication. We suggest that besides its high response rate in systemic relapsed/refractory HCL, vemurafenib may offer benefits for patients with CNS involvement who are refractory to conventional chemotherapies and can achieve a durable response. Further investigation is needed to potentially establish vemurafenib as a first-line treatment option for HCL patients with CNS involvement.
EXTH-28. ISOCITRATE DEHYDROGENASE MUTATIONS PREDICT SENSITIVITY TO HISTONE DEACETYLASE INHIBITION AND ENHANCED HISTONE ACETYLATION DYNAMICS ONLY IN THE CONTEXT OF GLIOMA
Authors: Thomas Sears, Michael Drumm, Wenxia Wang, Craig Horbinski
Journal: Neuro-Oncology (2023)

Abstract Isocitrate dehydrogenase 1/2 mutations (IDHmut) define a subtype of glioma with profound epigenetic dysregulation through genomic hypermethylation. IDHmut gliomas are incurable and fatal, demonstrating new treatments are needed. These mutations are common in other solid tumors, including chondrosarcoma (CS) and intrahepatic cholangiocarcinoma (ICC). Histone deacetylase (HDAC) enzymes compose a class of epigenetic drug targets utilized clinically to treat cancer, but their potential against IDHmut gliomas has not been extensively studied. We previously showed that IDHmut glioma cultures exhibit pronounced sensitivity to the effects mediated by the FDA-approved HDAC inhibitor (HDACi) panobinostat. Here, we integrate proliferation and cytoxicity data to show that this effect is unique to gliomas. In the context of histone H3 acetylation (H3KAc), panobinostat increased H3KAc, on average, by 7.6-fold and 30.5-fold in IDHwt and IDHmut glioma cultures, respectively (p&amp;lt; 0.001). This difference in HDACi-mediated H3KAc based on IDH status was not significant for CS and ICC. IDHmut gliomas are more sensitive two other FDA-approved HDACis: belinostat and vorinostat. RNA-Seq analysis showed that panobinostat more greatly affected gene expression in IDHmut glioma cells, particularly in the context of gene downregulation. Similarly, H3KAc ChIP-Seq showed a decrease in promoter histone acetylation moreso in IDHmut glioma cultures treated with panobinostat: there is an average loss of 1,236 and 14,759 H3KAc peaks at gene promoters in IDHwt and IDHmut cultures, respectively. This suggests that IDHmut gliomas exhibit enhanced histone acetylation dynamics in response to HDACi. Furthermore, using a PDX glioma model, we show that only mice engrafted with IDHmut glioma exhibit a significant survival increase in response to the HDACi belinostat: median survival was extended by 14 days in IDHmut glioma-bearing mice (p= 0.01), whereas belinostat extended median survival by 4 days in IDHwt glioma-bearing mice (p= 0.11). These results suggest that HDACi may be an effective in treating IDHmut gliomas.
NIMG-05. CHARACTERIZATION OF LONG-TERM METABOLIC CHANGES OF BRAIN METASTASES AFTER TREATMENT WITH STEREOTACTIC RADIOSURGERY USING SERIAL FET PET IMAGING
Authors: Michael Wollring, Carsten Lowis, Gabriele Stoffels, Jan-Michael Werner, Eren Celik, Christian Baues, Maximilian Ruge, Daniel Ruess, Gereon Fink, Karl-Josef Langen, Philipp Lohmann, Norbert Galldiks
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In the present study, we characterized the long-term metabolic changes of brain metastases after treatment with stereotactic radiosurgery (SRS) by serial PET imaging using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). We hypothesized that this approach is of considerable clinical value in differentiating between radiation-induced changes and local brain metastasis relapse. Patients and METHODS From 2010-2020, we retrospectively identified patients with brain metastases from solid extracranial primary tumors who (i) were treated with SRS with or without concurrent immunotherapy using checkpoint inhibitors, (ii) had equivocal MRI findings after SRS, and (iii) subsequently underwent two or more additional FET PET scans during follow-up for long-term evaluation. Mean tumor-to-brain ratios (TBR) were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses. Diagnoses were confirmed by neuropathological evaluation (29%) or clinicoradiologically (71%). RESULTS We identified 14 patients with 42 FET PET scans (median number, 3; range, 2-4). Concurrent to SRS, 4 patients (29%) were treated with checkpoint inhibitors. Following SRS, equivocal MRI findings occurred after a median time of 7 months (range, 2-62 months). Subsequently, FET PET scans were acquired over a median 16 months (range, 7-99 months). Nine patients (64%) had radiation-induced changes, and five had local brain metastases relapse. TBRs calculated from the last available FET PET scan showed the highest accuracy (93%) in identifying radiation-induced changes (threshold, 1.95; P=0.011). In lesions consistent with local brain metastases relapse, TBR increased considerably over time (median increase, 17%; range, 11% - 32%). In contrast, in lesions considered as radiation-induced changes, TBR remained stable or even decreased (median change, -4%; range, -44% - 11%). The TBR evolution over time significantly differed between the two groups (P=0.011). CONCLUSIONS Serial FET PET imaging has a high diagnostic accuracy for characterizing long-term changes of brain metastases after treatment with stereotactic radiosurgery.
NIMG-66. RADIOGENOMICS-BASED HETEROGENEITY ANALYSIS OF GLIOBLASTOMA REVEALS MR IMAGING PHENOTYPICAL CHARACTERIZATION OF EGFR MUTATIONS
Authors: Fanyang Yu, Jun Guo, Anahita Fathi Kazerooni, Hamed Akbari, Erik Toorens, Chiharu Sako, Elizabeth Mamourian, Stephen J Bagley, Zev Binder, Robert A Lustig, Steven Brem, Donald M O'Rourke, Tapan Ganguly, Spyridon Bakas, MacLean P Nasrallah, Pratik Chaudhari, Christos Davatzikos
Journal: Neuro-Oncology (2023)

Abstract PURPOSE EGFR is one of the most frequently altered genes in glioblastoma, while also being an attractive therapeutic target for treatment. Having in vivo, imaging-based markers of EGFR mutations, and as well as characterizing molecular heterogeneity, are important for patient management and stratification into trials. Toward this end, we present deep learning models of imaging signatures of EGFR mutations built from MRI. METHODS Our cohort consists of 286 glioblastoma patients with multi-parametric MRI (mpMRI) scans (T1, T1-Gd, T2, T2-FLAIR, DSC, DTI). Radiomics features, including histograms, morphologic and textural descriptors, were first derived. Genomic information was determined from a targeted next generation sequencing (NGS) panel. We jointly trained a variational auto-encoder and a multi-label classifier for predicting 4 key driver genes EGFR, NF1, PTEN, TP53 to learn a latent representation reflecting the molecular heterogeneity in the dataset. The latent representation was analyzed using principal component analysis (PCA). We calculated the Euclidean distance between imaging features of tumors with EGFR plus 1 of the other 3 mutations, from those of tumors having only EGFR mutations. We also analyzed the imaging signatures and variant allele frequencies (VAFs) of individuals with multiple (typically 3-4) resected tissue samples (n=49). RESULTS Co-occurrence of mutations in any of NF1, PTEN, TP53 genes with EGFR mutations resulted into dominance of imaging signatures of these other mutations over that of EGFR mutations. Interestingly, tumors with homogeneously high VAFs in EGFR mutations (n=3) exhibit strong phenotypical difference from the exclusive EGFR mutated group, while individuals with heterogeneous EGFR mutations (n=4) do not show such differences. CONCLUSION Our preliminary findings suggest EGFR imaging characteristics can be dominated by those of other co-occurring mutations. Tumors with homogeneously high VAFs, potentially indicating presence of germline EGFR mutations, lead to relatively distinct imaging phenotypes.
CCRG-03. KAT5 REGULATES DEVELOPMENTAL TRANSITIONS AND CELLULAR HETEROGENEITY IN AN <i>IN VIVO</i> MODEL OF GLIOBLASTOMA
Authors: Anca Mihalas, Christine Cucinotta, Sonali Arora, Dayoung Kim, Toshio Tsukiyama, Christopher Plaisier, Anoop Patel, Patrick Paddison
Journal: Neuro-Oncology (2023)

Abstract In solid tumors, G0-like states are likely critical for maintaining developmental hierarchies and cellular heterogeneity and promoting tumor growth/recurrence, yet little is known about tumor G0 states or regulation of their ingress/egress. To discover G0-like states and their regulators for glioblastoma (GBM), we previously performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) for genes that trap cells in G0 when inhibited. We identify the protein acetyltransferase KAT5 as a key regulator of GBM G0 ingress/egress. Here, we show in an in vivo GSC-derived orthotopic xenograft model that KAT5 regulates transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states. We show that KAT5 activity suppresses the emergence of non-dividing subpopulations with oligodendrocyte progenitor and radial glial cell characteristics. With regard to chromatin regulation, we show that loss of KAT5 activity alters sites of mixed epigenetic valency (which have both activating and repressive marks in bulk tumor populations) to promote emergence of OPC/RG G0-like populations in tumors. Our data reveal KAT5-associated transcriptional and epigenetic changes in tumors, which indicate that KAT5 activity biases cell state distribution away from OPC and RG-like subpopulations. In addition, loss of KAT5 resulted in a less invasive phenotype and prolonged survival of mice harboring orthotopic xenografts.
CTNI-74. ON-TRK: A NON-INTERVENTIONAL STUDY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION SOLID TUMORS
Authors: Ghazaleh Tabatabai, Jonathan Trent, Silvia Novello, Francesco Passiglia, Domnita-Ileana Burcoveanu, Ricarda Norenberg, Theodore Laetsch
Journal: Neuro-Oncology (2023)

Abstract Increasingly, health authorities and the medical community are investing resources into evaluating real-world data (RWD) on precision biomarker-based treatments. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pediatric and adult patients with various cancers. ON-TRK (NCT04142437) is an ongoing non-interventional post-approval study that is critical in gaining RWD on the treatment of patients with TRK fusion cancer and will contribute to the broader understanding of personalized therapy. This open-label, global, multi-cohort, prospective study will enroll up to 300 pediatric and adult patients with TRK fusion cancer scheduled to receive larotrectinib, including ≥ 30 pediatric patients. Patients with cancer harboring NTRK gene fusions, detected locally, are eligible. Patients who have had prior TRK inhibitor therapy and patients with NTRK genomic alterations other than functional gene fusions are excluded. Decisions on the dose and duration of treatment are at the discretion of the treating physician. The primary endpoint is safety, including specific long-term parameters in pediatric patients. Secondary endpoints include: efficacy (objective response rate, disease control rate, time to response, duration of response, progression-free survival, and overall survival), dosing patterns and long-term effects of larotrectinib in pediatric patients. The effects of larotrectinib on growth and developmental milestones in pediatric patients will be reported, including change in height and weight from baseline, age at adrenarche for males and menarche for females, number and percentage of patients with abnormal Tanner stages, and abnormal neurological assessments. All variables will be analyzed using descriptive statistics. Pediatric and adult patients will be followed for ≥ 5 years and ≥ 2 years, respectively, unless lost to follow-up, withdrawal, or death. Enrollment is ongoing worldwide; 24 patients with primary CNS cancer have been enrolled to date.
BIOM-64. A PROGNOSTIC SCORING SYSTEM FOR IMMUNODEFICIENCY-ASSOCIATED PRIMARY CNS LYMPHOMAS: AN INTERNATIONAL MULTI-CENTER STUDY
Authors: Philipp Karschnia, Benjamin-Leon Traub, Sofia Doubrovinskaia, Benjamin Richter, Sabine Seidel, Luis Kuschel, Felix Hinz, Kai Rejeski, Sebastian F Winter, Katharina Müller, Stefanie Quach, Christel Herold-Mende, Tobias Kessler, Felix Sahm, Uwe Schlegel, Michael Platten, Jorg Dietrich, Louisa von Baumgarten, Joachim Baehring, Wolfgang Wick, Leon Kaulen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Immunodeficiency-associated (ID-) primary CNS lymphomas (PCNSL) were introduced as a distinct entity in the 2021 World Health Organization classification of brain tumors. Given their rarity, larger clinical studies and prognostic models to guide management are lacking. METHODS PCNSL, newly diagnosed between 2004-2023 at six centers in the USA and in Germany, were retrospectively analyzed for concurrent immunodeficiency. Clinical, radiological, and pathological data were collected and assessed for prognostic significance using univariate and multivariate analyses. RESULTS Among 1112 patients with newly diagnosed PCNSL, 93 (8.4%) were identified as ID-PCNSL. Median age at diagnosis was 57 years and most tumors (66%) stained positive for Epstein-Barr virus (EBV). In addition to immune reconstitution, tumor-directed treatments were administered in 91/93 patients. These included chemotherapy (87%), radiation (25%), and autologous stem cell transplantation (14%). Outcome varied with a median overall survival (OS) of 46 months (range: 1-206 months). Age ≥ 60 years, Karnofsky performance status (KPS) &amp;lt; 70, EBV positivity, and non-rituximab or -methotrexate-based chemotherapy were associated with shorter OS on multivariate analysis adjusting for clinical and demographic factors. A prognostic scoring system was designed based on the sum of treatment-unrelated (age, KPS, EBV) unfavorable factors. The resulting score was highly prognostic and stratified ID-PCNSL into four subgroups: median OS was not reached, 90, 26, and 1 months (p &amp;lt; 0.0001) in cases with zero, one, two, or three unfavorable factors, respectively. Prognostic value was retained when limiting analysis to patients (n = 53), who had received HD-MTX and rituximab combination chemotherapy, with median OS of 98, 90, 46 and 4 months (p &amp;lt; 0.0001). CONCLUSIONS EBV was associated with inferior outcome in ID-PNCSL, which may reflect peculiar genetic alterations. An easily-applicable prognostic score based on three variables (age, KPS, EBV) allowed ID-PCNSL stratification into four risk groups. Prospective validation and therapeutic relevance warrant further investigation.
STEM-08. OVERCOMING GLIOBLASTOMA STEM CELL RESISTANCE TO RADIATION THROUGH TARGETING THIOREDOXIN REDUCTASE 1
Authors: Fatemeh Jamali, Katherine Lan, Siham Sabri, Bassam Abdulkarim
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma, the most aggressive primary tumor of the central nervous system, presents challenges due to its resistance to standard treatment, including radiation therapy (RT). Glioblastoma stem cells (GSCs), known for their chemo-radioresistance, employ adaptive mechanisms to counteract therapy-induced reactive oxygen species (ROS) levels. This includes modulating the activity of thioredoxin (Trx), a key player in the redox system. Furthermore, GSCs exhibit enhanced DNA repair capacity by upregulating DNA repair proteins, such as RAD51 to survive following ROS-induced DNA damage in response to radiation. Our TCGA analysis revealed elevated expression of thioredoxin reductase 1 (TrxR1) in patients diagnosed with GBM and a significant positive correlation between TrxR1 and RAD51. We hypothesized that GSCs might enhance their antioxidant capacity following RT to suppress RT-induced ROS elevation. Hence, combining RT with TrxR1 inhibitors might overcome GSCs radioresistance while reducing RAD51 expression. Auranofin (Au), a drug FDA-approved for rheumatoid arthritis inhibits TrxR1 activity with subsequent ROS increase. We assessed Au cytotoxicity on GSCs with and without ionizing radiation using Alamar Blue and neutrosphere formation assays and ROS assay for quantitative analysis of ROS levels. We evaluated the molecular mechanisms associated with Au and IR-induced cell death in GSCs using western blotting analysis. Our findings suggest that resistance of GSCs to IR was accompanied with increased expression of TrxR1 and RAD51. On the other hand, Au alone significantly decreased GSC viability and neurosphere formation and sensitized GSCs to IR within the nanomolar range (significantly lower than the corresponding IC50s). Au alone and combined with IR increased ROS, while expression of both RAD51 and TrxR1 was decreased. Our study provides insights into repurposing the TrxR1 inhibitor, Au and its combination with RT as a novel therapeutic strategy to overcome GSC radioresistance and ultimately improve the dismal outcome of patients diagnosed with GBM.
SURG-42. FACTORS INFLUENCING TUMOR RECURRENCE AFTER RESECTION OF SKULL-BASE MENINGIOMAS
Authors: Sabrina Begley, Josh McBriar, Jung Park, Amir Dehdashti
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Resection of skull-base meningiomas is challenging, given the proximity of and adherence to neurovascular structures. We characterize the benefits of neurosurgical resection of meningiomas, comparing clinical and surgical outcomes based upon tumor location within and outside the skull base. METHODS Data were retrospectively collected from 85 patients who underwent surgical resection of meningioma between 2008 – 2018, for whom long-term follow-up was available. Outcomes were compared between locations: non-skull base, anterior fossa, middle fossa, and posterior fossa. Logistic regression analysis was used to analyze pre-operative and pathologic factors influencing recurrence. RESULTS Forty-five (54.1%) tumors were located on the skull base: 29 anterior fossa, 22 middle, and 6 posterior. Simpson grade 1 or 2 resection was achieved in 63 patients. Mean Ki-67 showed a statically significant difference between all tumor locations: non-skull base (7.1), anterior fossa (4.0), middle fossa (10.8), posterior fossa (2.8) (p = 0.009). Simpson grade differed significantly by tumor location with percentage of Simpson grade 1 resections as follows: non-skull base supratentorial (45.7%), non-skull base infratentorial (0.0%), anterior (71.5%), middle (30.0%), posterior (16.7%) (p = 0.022). Tumors recurred in 11 patients with recurrence differing significantly between locations: non-skull base (18.2%), anterior (3.8%), middle (36.4%), posterior (0.0%) (p = 0.046). Median progression-free survival was 115.5 months and did not significantly differ by location. Larger tumor volumes (p = 0.018), Simpson grade 3 resection (p = 0.016), and increased Ki67 (p = 0.046) were associated with higher recurrence risk. No variables predicted post-operative neurological deficits. CONCLUSIONS High variability exists within skull-base meningiomas, depending on the cranial fossa of origin. Location may impact the molecular make-up, extent of resection, and patient outcomes. Due to the high-risk anatomy of the skull base, confirming these predictors of recurrence is vital to optimize initial treatment and decrease the risk associated with salvage treatment.
EPID-09. ASSOCIATION BETWEEN VIRAL INFECTIONS AND GLIOMA RISK: A TWO-SAMPLE BI-DIRECTIONAL MENDELIAN RANDOMIZATION ANALYSIS
Authors: Wenzhuo Yang, Sheng Zhong, Haoqun Xie, Zhiyun Zhang, Ke Sai, Yonggao Mou
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioma is one of the leading causes of brain tumors, but few etiologic factors of primary gliomas were identified. Previous observational research has shown an association between viral infection and glioma risk. Here, we sought to use Mendelian Randomization (MR) analysis to explore the direction and magnitude of the causal relationship between viral infections and glioma. METHODS We conducted a two-sample bi-directional MR analysis using Genome-Wide Association Study (GWAS) data. Summary statistics data of glioma were collected from the most extensive meta-analysis GWAS involving 12,488 cases and 18,169 controls. Single Nucleotide Polymorphisms (SNPs) associated with the exposures were used as instrumental variables to estimate the causal relationship between glioma and twelve types of viral infections from corresponding GWAS data. In addition, sensitivity analyses were performed. RESULTS After correcting for multiple tests and sensitivity analysis, we detected that genetically predicted VZV infection significantly decreased the risk of lower-grade glioma (LGG) development (OR=0.85, 95% CI: 0.76-0.96, P=0.0066, FDR=0.0396). No causal effects of the other eleven viral infections on glioma and reverse causality were detected. CONCLUSIONS Our research is one of this field's first and most significant studies. We showed robust evidence supporting that genetically predicted VZV infection reduces the risk of LGG. The findings from our research are a big step forward in understanding the etiology of glioma.